The absence of accepted simple screens with predictive validity is one of several barriers to the discovery of novel drugs for alcohol dependence. For example, modulation of the glutamate - NMDA receptor (NMDAR) is a clear molecular target for drugs that might decrease relapse rates and/or reduce alcohol-associated neurotoxicity, but there is no accepted way of preclinically evaluating such drugs for potential value against these therapeutic targets. The original aims of the project were (a) to establish a hierarchy of screens for these therapeutic targets, validating the screens with drugs believed or known to be effective, and (b) to generate a library of novel active compounds to be evaluated using the screening hierarchy. The screening hierarchy is almost complete, with the exception of validation of behavioral screens for alcohol-associated neurotoxicity. Additionally, over 600 compounds based on endogenous modulators of the NMDAR have been synthesized and screened for appropriate molecular effects. Two novel and potent structural series have emerged, based on tryptamine and agmatine derivatives, which are believed to modulate NMDAR function in different ways. Similar, naturally occurring, compounds have previously been demonstrated to reduce drug-seeking behavior and/or to be neuroprotective. Some of the novel synthetic compounds have now been screened for neuroprotective properties in vitro, and anti-seizure properties during withdrawal in vivo. Active compounds will next be evaluated for effects on rat drinking in an "alcohol deprivation effect" paradigm, for effects on mouse behavior in a "conditioned pseudowithdrawal" paradigm, and in behavioral screens of neuroprotection in rats when these have been validated. The specific aims of this competing renewal are thus to complete the screening hierarchies, and to continue to test the two novel compound series in these. Additionally, since it may now be possible to identify novel compounds with potential therapeutic value in alcohol dependence, further research is necessary to protect the intellectual property in these, and to bring them to the stage of toxicity testing prior to clinical evaluation. The overall objective remains to demonstrate the legitimacy of this approach to medications development in alcohol dependence by establishing the reproducibility and predictive validity of the screening hierarchies for evaluation of novel compounds. Even if this objective is not fully achieved, the novel compounds, and their performance in the different screens, will help to elucidate the roles of NMDARs and their modulators in relapse, and in alcohol-associated neurotoxicity.